Methods of treating select neuronal inflammatory disorders using hydroxyalkylquinolines

ABSTRACT

Methods of treating select mammalian disorders using a leukotriene antagonist are described. The methods involve administering to the mammal a therapeutically effective amount of a compound having the formula:  
                 
 
     The methods may be employed to treat disorders such as traumatic spinal cord injury, graying of the scalp hair, herpes simplex, herpes zoster, Bell&#39;s palsy, multiple sclerosis, and Gillian-Barre.

REFERENCE TO RELATED APPLICATION

[0001] This application is a division of commonly owned co-pending U.S.application Ser. No. 09/657,333 filed on Sep. 7, 2000.

TECHNICAL FIELD

[0002] This invention relates to methods of treating neuronalinflammatory disorders.

THE INVENTION

[0003] Certain hydroxyalkylquinoline acids and ether acids, as well astheir corresponding salts, are known to be leukotriene antagonists. See,e.g., U.S. Pat. Nos. 5,266,568, 5,270,324, 5,428,033, 5,565,473 and5,856,322. As noted in the foregoing patents, these compounds are knownto be useful in the treatment of pulmonary disorders including diseasessuch as asthma, chronic bronchitis, and related obstructive airwaydiseases, allergies and allergic reactions such as allergic rhinitis,contact dermatitis, allergic conjunctivitis, and the like, inflammationsuch as arthritis or inflammatory bowel disease, pain, skin disorderssuch as psoriasis, atopic eczema, and the like, cardiovascular disorderssuch as angina, myocardial ischemia, hypertension, platelet aggregationand the like, renal insufficiency arising from ischemia induced byimmunological or chemical (cyclosporin) etiology, migraine or clusterheadache, ocular conditions such as uveitis, hepatitis resulting fromchemical, immunological or infectious stimuli, trauma or shock statessuch as burn injuries, endotoxemia and the like, allograft rejection,prevention of side effects associated with therapeutic administration ofcytokines such as Interleukin II and tumor necrosis factor, chronic lungdiseases such as cystic fibrosis, bronchitis and other small andlarge-airway diseases, cholecystitis; erosive gastritis; erosiveesophagitis; diarrhea; cerebral spasm; premature labor; spontaneousabortion; dysmenorrhea; ischemia; noxious agent-induced damage ornecrosis of hepatic, pancreatic, renal, or myocardial tissue; liverparenchymal damage caused by hepatoxic agents such as CCl₄ andD-galactosamine; ischemic renal failure; disease-induced hepatic damage;bile salt induced pancreatic or gastric damage; trauma- orstress-induced cell damage; glycerol-induced renal failure; andcytoprotective activity in gastrointestinal mucosa and prevention ofgastric lesions.

[0004] However, it has now been found that select hydroxyalkylquinolineacids (and the pharmaceutically acceptable salts thereof) are useful inthe treatment of conditions which are believed to be caused by neuronalinflammation. Neuronal inflammatory disorders share a particularpathophysiology in relation to the select hydroxyalkylquinolinecompounds. In particular, compounds which have the biological propertyin mammals of acting as “leukotriene antagonists” are particularlyeffective in the treatment of neuronal inflammatory disorders.

[0005] Furthermore, it has been discovered that certainhydroxyalkylquinoline acids and their salts can be utilized to treatsome disorders which have not been conclusively shown to originate withinflamed neurons. One particularly painful and debilitating group ofdisorders, members of which have responded remarkably well to treatmentwith hydroxyalkylquinolines, are those commonly referred to asrepetitive motion disorders. In the case of such disorders,hydroxyalkylquinolines not only effectively relieve the symptoms, butoften effect a complete cure, allowing return to the same repetitivemotion-type activity which caused the disorder without incidence ofrelapse. Regardless of any previous association with repetitive motion,the disorders referred to hereinafter are considered to be neuronalinflammatory disorders for the purposes of this description, even if ithas not been conclusively established that the symptoms of theparticular disorder are caused or mediated by inflamed neuronalelements.

[0006] Disorders which are known to be neural inflammatory in natureinclude viral infections, such as Herpes simplexes I and II. The presentinvention has demonstrated success in the treatment of symptoms of viralinfections. Thus a method is provided for the treatment and/or the longterm suppression of symptoms of viral infection such as skin lesions andpostherpetic neuralgia, as well as other symptoms of viral infectionwhich are neuronal inflammatory in origin.

[0007] The present invention has also been successful in halting thecourse of a condition which has long been suspected by the presentinventor to be neuronal inflammatory in origin: the progressive grayingof the scalp hair. Thus the present invention provides a method for thetreatment and/or long-term suppression of symptoms of scalp hairconditions which are neuronal inflammatory in nature, such asprogressive graying.

[0008] In addition, the present invention provides a method for treatingand/or suppression of symptoms of neuronal inflammatory conditions whoseetiology is often partially or fully unknown, some of which are Multiplesclerosis, Guillian-Barre syndrome and Bell's palsy.

[0009] Furthermore, the present invention provides a method for thetreatment of neuronal inflammatory conditions which originate withexternal factors, such conditions including traumatic spinal injury.

[0010] Moreover, the present invention provides a method for treatmentand long term suppression of symptoms associated with disorderspreviously considered repetitive motion disorders.

[0011] The above-described methods comprise administering, to a mammalin need of such treatment, a therapeutically effective amount of acompound having a chemical structural formula as follows:

[0012]

[0013] wherein:

[0014] R¹ is H, halogen, —CF₃, —CN, —NO₂, or N₃;

[0015] R² is lower alkyl, lower alkenyl, lower alkynyl, —CF₃, —CH₂F,—CHF₂, CH₂CF₃, substituted or unsubstituted phenyl, substituted orunsubstituted benzyl, substituted or unsubstituted 2-phenethyl, or twoR² groups joined to the same carbon to form a carbocyclic ring of up to8 members;

[0016] R³ is H or R²;

[0017] R⁴ is halogen, —NO₂, —CN, —OR³, —SR³, NR³R³, NR³C(O)R⁷ or R³;

[0018] R⁵ is H, halogen, —NO₂, —N₃, —CN, —SR², —NR³R³, —OR³, loweralkyl, or —C(O)R³;

[0019] R⁶ is —(CH₂)_(s)—C(R⁷R⁷)—(CH₂)_(s)—R⁸ or —CH₂C(O)NR¹²R¹²;

[0020] R⁷ is H or C₁-C₄ alkyl;

[0021] R⁸ is the radical W—R⁹;

[0022] R⁹ contains up to 20 carbon atoms and is (1) an alkyl group or(2) an alkylcarbonyl group of an organic acyclic or monocycliccarboxylic acid;

[0023] R¹¹ is lower alkyl, —C(O)R¹⁴, unsubstituted phenyl, orunsubstituted benzyl;

[0024] R¹² is H, or R¹¹;

[0025] R¹³ is lower alkyl, lower alkenyl, lower alkynyl, —CF₃ orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl;

[0026] R¹⁴ is H or R¹³;

[0027] R¹⁶ is H, C₁-C₄ alkyl, or OH;

[0028] R¹⁷ is lower alkyl, lower alkenyl, lower alkynyl, or substitutedor unsubstituted phenyl, benzyl, or 2-phenethyl;

[0029] R¹⁸ is lower alkyl, lower alkenyl, lower alkynyl, —CF₃ orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl;

[0030] R¹⁹ is lower alkyl, lower alkenyl, lower alkynyl, —CF₃ orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl;

[0031] R²¹ is H or R¹⁷;

[0032] R²² is R⁴, CHR⁷OR³, or CHR⁷SR²;

[0033] m is 0-8;

[0034] m′ is 2 or 3;

[0035] n and n′ are independently 0 or 1,

[0036] p and p′ are independently 0-8;

[0037] m+n+p is 1-10 when r is 1 and X² is O, S, S(O), or S(O)₂;

[0038] m+n+p is 0-10 when r is 1 and X² is CR³R¹⁶;

[0039] m+n+p is 0-10 when r is 0;

[0040] m′+n′+p′ is 2-10;

[0041] r and r′ are independently 0 or 1;

[0042] s is 0-3;

[0043] Q¹ is —C(O)OR³, 1H (or 2H)-tetrazol-5-yl, —C(O)OR⁶,—C(O)NHS(O)₂R¹³, —CN, —C(O)NR¹²R¹², NR²¹S(O)₂R¹³, —NR¹²C(O)NR¹²R¹²,—NR²¹C(O)R¹⁸, —OC(O)NR¹²R¹², —C(O)R¹⁹, —S(O)R¹⁸, —S(O)₂R¹⁸,—S(O)₂NR¹²R¹², —NO₂, —NR²¹C(O)OR¹⁷, —C(NR¹²R¹²)═NR¹², —C(R¹³)═NOH;

[0044] Q² is OH;

[0045] W is O, S, or NR³;

[0046] X² and X³ are independently O, S, S(O), S(O)₂, or CR³R¹⁶; withthe proviso that at least one is S or SO₂:

[0047] Y is —CR³═CR³—

[0048] Z¹ and Z² are independently —HET(—R³—R⁵)—;

[0049] HET is the diradical of a benzene, a pyridine, a furan, or athiophene; or a pharmaceutically acceptable salt thereof. The term“pharmaceutically acceptable salt” refers to a salt that retains thedesired biological activity of the parent compound and does not impartany undesired toxicological effects, e.g., an acid or base additionsalt.

[0050] Preferred is a compound having a chemical structural formula asfollows:

[0051] wherein the substituents are as follows: * R¹ Y A B RS 7-Cl CH═CHSCH₂CHMeCO₂H (1,3-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂H (1,4-phe)CMe₂ OHRS 7-Cl CH═CH SCH₂CHEtCO₂ H (1,3-phe)CMe₂ OH RS 7-Cl CH═CH SCH₂CHEtCO₂ H(1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ OH S7-Cl C≡C SCH₂(S)CHMeCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHEtCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C S(CH₂)₂CO₂ H (CH₂)₂ (1,2-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NH₂ RS 7-Cl CH═CHSCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NHMe RS 7-Cl CH═CH SCH₂CHEtCO₂ H(CH₂)₂ (1,2-phe)CMe₂ NMe₂ RS 7-Br C≡C SCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂OH S 7-Cl CH═CH SCH₂CH(CH₂CH═CH₂)CO₂H (CH₂)₂ (1,2-phe)CMe₂ OH S 7-ClCH═CH SCH₂CHEtCO₂H (CH₂)₂(1,2-phe)C(CH₂OCH₂)OH

[0052] Particularly preferred as the compound is1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl)cyclopropaneace-tic acid or a pharmaceutically acceptable salt thereof,and in particular the monosodium salt thereof (i.e., montelukastsodium), which is the active ingredient in the pharmaceutical marketedby Merck & Co., Inc. under the trademark, Singulair®. This and relatedcompounds, including methods of producing such compounds, are describedin greater detail in U.S. Pat. No. 5,565,473, the disclosure of which isincorporated herein by reference.

[0053] This invention also provides an an article of manufacture forhuman pharmaceutical use, comprising packaging material and a containercomprising1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl)cyclopropaneace-tic acid or a pharmaceutically acceptable salt thereof,wherein said packaging material comprises a label which indicates thatsaid cyclopropaneacetic acid, or said pharmaceutically acceptable saltthereof, is suitable for treatment, or alleviation of symptoms, of oneor more disorders selected from the group consisting of carpal tunnel,cubital tunnel, tarsal tunnel, traumatic spinal cord injury, graying ofscalp hair, thoracic outlet, herpes simplex, herpes zoster, Bell'spalsy, multiple sclerosis, and Gillian-Barre.

[0054] These and other embodiments and features of the invention willbecome still further apparent from the ensuing description, examples andappended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0055] When utilizing hydroxyalkyl quinolines to treat theaforementioned conditions, the compound can be introduced into the bodyby oral administration, (i.e., by ingestion of a tablet, pill, liquidsuspension or the like), by sub-dermal injection, or other means. Iftaken orally, it is preferable to use a dose of about 4 to about 10milligrams per day. If administered by injection, it is preferable toutilize a dose of about 1 to about 10 milligrams per injection, about2-4 times per monthly. The entire daily dosage can be taken as a singledose, or it can be administered as two or more smaller doses taken atappropriate intervals. However, preferred dosages, preferred modes ofadministration, and subdivision of dosages vary somewhat with thecondition or disease for which treatment is sought. Suggestionspertaining to particular conditions are given below.

[0056] Hydroxyalkylquinoline compounds can be used for the relief ofsymptoms due to active viral infections. In particular, the activeingredient of Singulair® can relieve blisters and skin lesions suchas 1) skin lesions on the face, lip and oral mucosa overlying softtissue due to an active Herpes Simplex I infection (HSV-I); 2) skinlesions on the genitals and anus due to an active Herpes Simplex I(HSV-I) infection or Herpes Simplex II infection (HSV-II); and 3)variously located skin lesions due to an active infection of Herpeszoster (chicken pox virus). The standard oral dose of about 4 to about10 milligrams is appropriate for the treatment of existing blisters in apatient.

[0057] Hydroxyalkylquinolines can be administered at any time during thepresence of the blisters. However, best results are obtained whentreatment is initiated as soon as the initial symptoms of blistering aredetected.

[0058] It is preferable that the patient continue to take an effectiveamount of a composition of this invention until blisters and pain havesubsided. Treatment time can be expected to be in the range of fromabout 5 to about 10 days. In most cases, patient experiences completerelief in a time in the range of from about 2 to about 4 days.

[0059] Hydroxyalkylquinolines can also be used to treat or prevent orreduce the severity of the localized pain caused by viral infection,typically following the resolution of skin blisters. In particular, suchcompounds are effective in treating post-herpetic neuralgia such as isoften associated with chicken pox virus infection. The dosages and meansof administration are as noted in the first paragraph of the “DetailedDescription.” It is preferred that the dosages be administered orallyfor a period of two to four weeks. Treatment can be initiated at anytime after the appearance of blisters, from the first appearance tocrusting and resolution. However, the likelihood of complete preventionof neuralgia, as opposed to merely reducing its severity, is increasedwith promptness of treatment. It is preferred that the patient continuetreatment for the duration of the pain. In severe cases, it may beadvisable to administer continuous treatment. Most patients can beexpected to begin experiencing relief within from about 10 to about 21days.

[0060] Other symptoms of the aforementioned viral infections whichrespond to the administration of hydroxyalkylquinoline compounds are thelocalized itching, burning or tingling, often for prolonged periods,which accompany the infection and generally closely precede thedevelopment of blisters. The dosages and means of administration are asgiven in the first paragraph of the “Detailed Description.”

[0061] Furthermore, if hydroxyalkylquinoline compounds are administeredafter the onset of localized irritation (i.e., itching, burning ortingling), but before the onset of blistering, it can be used to preventblisters or reduce their severity. In order to prevent blistering, it ispreferable to begin treatment within about forty eight hours of theonset of the localized irritation, however, in some cases, even at latertimes, the administration of hydroxyalkylquinoline compounds can preventthe formation of blisters. The dosages and means of administration areas given in the first paragraph of the “Detailed Description.” It isadvisable to treat patient with hydroxy alkyl quinoline compounds untilthe localized irritation subsides, or, if sores develop, until the soresresolve.

[0062] Moreover, the administration of appropriate dosages ofhydroxyalkylquinoline compounds can be utilized for the long termmanagement of dormant viral infections. For example,hydroxyalkylquinoline compounds can effectively suppress the periodicappearance of stress-induced sores (often induced by overwork, toolittle sleep, etc.) in a patient with a latent HSV-I or HSV-IIinfection. A patient can be treated on a continual basis. The dosagesand means of administration are as given in the first paragraph of the“Detailed Description.”

[0063] However, long term suppression of virally-induced pain andblistering can be accomplished by treating the patient on a schedule ofintervals which anticipate 1) a sore forming cycle manifested by aparticular patient, or 2) stresses to which a patient is, will be, or islikely to be exposed. Examples of such stresses are trauma to self, afriend or a family member; occupational stresses; and the like.

[0064] In the inhibition of scalp hair graying, it is advisable to begintreatment before all the scalp hair has grayed. Preferably, only smallpatches of gray are present. Treatment is on a continuous basis, andinterruptions in treatment can result in the resumption of graying. Thedosages and means of administration are as given in the first paragraphof the “Detailed Description.”

[0065] Disorders such as Bell's Palsy, Gillian-Barre Syndrome andMultiple Sclerosis, the etiology of which is unknown and which arethought be the result of virus-initiated neural inflammation, are likelycandidates for treatment with hydroxyalkyl quinoline compounds. Thedosages and means of administration are as given in the first paragraphof the “Detailed Description.” It is preferable to treat Bell's Palsyand Gillian-Barre Syndrome with oral dosages immediately after the onsetof symptoms. In the case of Bell's Palsy, such symptoms include facialnumbness, weakness or lack of motor control in the facial muscles andlack of taste in the anterior portion of the tongue. A symptom ofGuillian-Barre Syndrome which can be expected to improve with theadministration of hydroxyalkylquinoline compounds is the accompanyingextensive muscular weakness.

[0066] In the case of Multiple Sclerosis, treatment withhydroxyalkylquinolines can be expected to reduce the severity ofsymptoms and number of relapses, the symptoms including, e.g., numbness,weakness and neurogenic pain. A preferred manner of treatment isintrathecal injection of hydroxyalkyl quinoline compounds at the time ofdiagnosis, with additional injections as long as patient manifestssymptoms. Those hydroxyalkylquinoline compounds which have the capacityto penetrate the blood-brain barrier can be administered orally. Withsuch compounds, it is most preferable that oral administration accompanyperiodic intrathecal injection. Such oral administration can beperformed daily, with injections as frequent as two to four times permonth.

[0067] Traumatic spinal cord injury can be expected to respond totreatment with hydroxyalkyl quinoline compounds. The dosages and meansof administration are as described above in the first paragraph of the“Detailed Description.” However, it is preferred to begin treatmentimmediately following the occurrence of spinal cord injury. Suchtreatment preferably consists of daily oral administration given inconjunction with high doses of intravenous and/or oral steroids. Suchtreatment preferably continues until such a time as the inflammatoryneuronal response to the injury, is maximally diminished or eliminated.

[0068] Hydroxyalkyl quinoline compounds can also be expected to beuseful in treating disorders, heretofore thought to have been caused byswelling of soft tissue and known as repetitive motion disorders, butwhich may be due instead to neuronal inflammation. In the treatment ofcarpal tunnel, cubital tunnel, tarsal tunnel and thoracic outletsyndromes, the dosages and means of administration are as given above inthe first paragraph of the “Detailed Description.” A preferred treatmentis the oral administration of hydroxyalkylquinoline compounds for fourto eight weeks and/or intermittently as symptoms occur. Anotherpreferred treatment is the injection of the standard injectable dose ofthe presently described leukotriene antagonists at or near the site ofneuronal compression. Such injections may be performed intermittently,or only once. The intended dose can be delivered as a single injection,or as a series of injections, each containing an amount of thehydroxyalkylquinoline which is less than the intended dose.

[0069] The pharmaceutical compositions of this invention may be packagedin a variety of ways depending upon the method used for administeringthe drug. Generally, an article for distribution includes packagingmaterial and a container which contains the pharmaceutical formulationin an appropriate form. Suitable containers are well-known to thoseskilled in the art and include materials such as bottles (plastic andglass), sachets, ampoules, plastic bags, metal cylinders, blister packs,silica gel desiccant canisters and the like. The container may alsoinclude a tamper-proof assemblage to prevent indiscreet access to thecontents of the package. In addition to the container, the articlefurther comprises packaging material comprised of a label deposited uponor packaged with the container, the label describing the contents of thecontainer and indicating that contents of the container is suitable fortreatment, or alleviation of symptoms, of one or more disorders selectedfrom the group consisting of carpal tunnel, cubital tunnel, tarsaltunnel, traumatic spinal cord injury, graying of scalp hair, thoracicoutlet, herpes simplex, herpes zoster, Bell's palsy, multiple sclerosis,and Gillian-Barre. The label may also include appropriate warnings.

[0070] Examples 1-7 demonstrate the effectiveness of a preferredhydroxyalkylquinoline acid (or the pharmaceutically acceptable saltthereof) in treating and/or suppressing the symptoms of repetitivetrauma disorders such as carpal tunnel, cubital tunnel, and thoracicoutlet syndromes.

EXAMPLE 1

[0071] A carpenter who was experiencing the symptoms of carpal tunnelsyndrome was treated with 10 mg of Singulair® per day, taken orally, forfour weeks. He continued to perform his daily occupational activitiesthroughout the period of treatment. He obtained complete remission ofsymptoms. Following cessation of treatment, the symptoms recurred.Patient was then treated for short courses of 10 mg of Singulair® perday, whenever symptoms were present, until symptoms subsided.

EXAMPLE 2

[0072] A patient who worked as a billing clerk had carpal tunnelsymptoms which had not responded to non-surgical methods of treatment.Patient was treated with Singulair® at 10 mg daily, taken orally. Aftersix weeks, she experienced complete resolution of her carpal tunnelsymptoms. Though she continued her occupational activities as a billingclerk, after forty weeks, she remained symptom-free.

EXAMPLE 3

[0073] A patient who works as a data entry clerk, experienced severecarpal tunnel symptoms. She ceased her occupational activities and begantreatment with Singulair® at 10 mg per day, taken orally. After fourweeks of therapy, her symptoms had completely resolved, and she returnedto work, continuing the Singulair® treatment. Upon recheck in two weeks,she remained symptom-free. At this time, treatment with Singulair® wasdiscontinued, and patient remained symptom-free thereafter.

EXAMPLE 4

[0074] Patient was an insurance clerk who experienced severe carpaltunnel symptoms which had not abated, even after carpal tunneldecompression surgery. For years following surgery, she had experiencedsevere carpal tunnel symptoms. After six weeks of therapy withSingulair® at 10 mg per day taken orally, she experienced completeresolution of her symptoms, despite the fact that she continued routineoccupational activities. When treatment was stopped, her symptomsrapidly returned. Symptoms abated with resumption of treatment, and withcontinuing treatment, she remains symptom-free.

EXAMPLE 5

[0075] Patient was an assembly line worker at an automobile productionfacility who was experiencing symptoms of carpal tunnel syndrome wastreated with 10 mg of Singulair® per day taken orally. He continued toperform his daily occupational activities and noted that his symptomsabated after six weeks of treatment. He required continuous treatmentwith 10 mg of Singulair® per day taken orally to maintain remission ofhis symptoms.

EXAMPLE 6

[0076] Patient was a golfer who experienced symptoms of cubital tunnelsyndrome. Lengthy treatments with multiple non-steroidalanti-inflammatory drugs, cessation of the causative activity (golf), anduse of elbow splints failed to relieve patient's symptoms. Patient wastreated with Singulair® at 10 mg daily, taken orally. Symptoms wereentirely abated after four weeks. No further treatment was requireddespite his return to his regular golfing activity.

EXAMPLE 7

[0077] Patient exhibited symptoms of thoracic outlet syndrome includinga pain radiating down the left arm, a burning sensation beneath the leftscapula, weakness of the left hand, and intermittent numbness of theleft hand. Patient was treated with Singulair® at 10 mg per day takenorally. After four weeks, symptoms had completely resolved. No furthertreatment was required.

[0078] Examples 8-12 demonstrate the effectiveness of a preferredhydroxyalkylquinoline acid (or the salt thereof) in the treatment ofHerpes simplex I and II (HSV I and II), a latent latent viral disease.

EXAMPLE 8

[0079] Patient had recently discontinued use of Singulair® as atreatment for asthma. Five days later, patient developed a cold sore,possibly caused by excessive exposure to ultraviolet light. The coldsore resolved in three days after treatment with Singulair® was resumed.The rate of resolution was faster than the resolution of previous soreswhich were treated with antiviral treatments such as those marketedunder the trademarks Zovirax® or Famvir® (approximately seven to tendays). During the subsequent two years, patient took Singulair® on adaily basis (10 mg, twice a day). In that time period, patient wasexposed to levels of ultraviolet light which were as high as those whichhad possibly induced the sore, yet no new sore developed.

EXAMPLE 9

[0080] A patient who had a history of developing an average of two coldsores per month was treated with Singulair® at 10 mg per day, takenorally. No cold sore was present at the time therapy was started.Patient remained free of cold sores with continuous daily treatment forten months. Within five days of termination of treatment, a cold soredeveloped. The patient restarted treatment, and remained free of coldsores as of thirteen months after resumption of treatment.

EXAMPLE 10

[0081] Patient had post-herpetic neuralgia due to a latent Herpesinfection. Neuralgia developed despite initial treatment with anti-viralagents as per standard treatment recommendations. Patient begantreatment with Singulair® (10 mg per day, taken orally). Thepost-herpetic neuralgia resolved in ten days. No further treatment wasrequired.

EXAMPLE 11

[0082] Patient had postherpetic neuralgia due to a latent Herpesinfection. Neuralgia developed despite initial treatment with anti-viralagents as per standard treatment recommendations. Patient begantreatment with Singulair® (10 mg per day, taken orally). Thepost-herpetic neuralgia resolved in 14 days. No further treatment wasrequired.

[0083] Example 12 demonstrates the effectiveness of a preferredhydroxyalkylquinoline acid (or the salt thereof) in inhibiting thenatural graying process of scalp hair.

EXAMPLE 12

[0084] Patient had noted the onset of graying of the temple regions ofhis hair. No progression of the graying process in the temple region ordevelopment of graying in any other scalp areas noted after two yearsand four months of continuous treatment with Singulair® (10 mg per day,taken orally).

[0085] The disclosure of each patent and patent application referencedabove is incorporated herein by reference to the fullest extent and forall purposes as may be permitted by law.

[0086] This invention is susceptible to considerable variation in itspractice. Therefore, the foregoing description is not intended to limit,and should not be construed as limiting, the invention to the particularexemplifications presented hereinabove. Rather, what is intended to becovered is as set forth in the ensuing claims and the equivalentsthereof permitted as a matter of law.

That Which is Claimed is:
 1. A method of treating a disorder, selectedfrom the group consisting of traumatic spinal cord injury, graying ofscalp hair, herpes simplex, herpes zoster, Bell's palsy, multiplesclerosis, and Gillian-Barre, in a mammal comprising administering to amammal in need of such treatment a therapeutically effective amount of acompound having the formula:

wherein: R¹ is H, halogen, —CF₃, —CN, —NO₂, or N₃; R² is lower alkyl,lower alkenyl, lower alkynyl, —CF₃, —CH₂F, —CHF₂, CH₂ CF₃, substitutedor unsubstituted phenyl, substituted or unsubstituted benzyl,substituted or unsubstituted 2-phenethyl, or two R² groups joined to thesame carbon to form a carbocyclic ring of up to 8 members; R³ is H orR²; R⁴ is halogen, —NO₂, —CN, —OR³, —SR³, NR³R³, NR³C(O)R⁷ or R³; R⁵ isH, halogen, —NO₂, —N₃, —CN, —SR², —NR³R³, —OR³, lower alkyl, or —C(O)R³;R⁶ is —(CH₂)_(s)—C(R⁷R⁷) —(CH₂)_(s)—R⁸ or —CH₂C(O)NR¹²R¹²; R⁷ is H orC₁-C₄ alkyl; R⁸ is the radical W—R⁹; R⁹ contains up to 20 carbon atomsand is (1) an alkyl group or (2) an alkylcarbonyl group of an organicacyclic or monocyclic carboxylic acid; R¹¹ is lower alkyl, —C(O)R¹⁴,unsubstituted phenyl, or unsubstituted benzyl; R¹² is H, or R¹¹; R¹³ islower alkyl, lower alkenyl, lower alkynyl, —CF₃ or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁴ is H or R¹³; R¹⁶ is H,C₁-C₄ alkyl, or OH; R¹⁷ is lower alkyl, lower alkenyl, lower alkynyl, orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁸ islower alkyl, lower alkenyl, lower alkynyl, —CF₃ or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁹ is lower alkyl, loweralkenyl, lower alkynyl, —CF₃ or substituted or unsubstituted phenyl,benzyl, or 2-phenethyl; R²¹ is H or R¹⁷; R²² is R⁴, CHR⁷OR³, or CHR⁷SR²;m is 0-8; m′is 2 or 3; n and n′ are independently 0 or 1, p and p′ areindependently 0-8; m+n+p is 1-10 when r is 1 and X² is O, S, S(O), orS(O)₂; m+n+p is 0-10 when r is 1 and X² is CR³R¹⁶; m+n+p is 0-10 when ris 0; m′+n′+p′ is 2-10; r and r′ are independently 0 or 1; s is 0-3; Q¹is —C(O)OR^(3,) 1H (or 2H)-tetrazol-5-yl, —C(O)OR⁶, —C(O)NHS(O)₂R¹³,—CN, —C(O)NR¹²R¹², NR²¹S(O)₂R¹³, —NR¹²C(O)NR¹²R¹², —NR²¹C(O)R¹⁸,—OC(O)NR¹²R¹², —C(O)R¹⁹, —S(O)R¹⁸, —S(O)₂R¹⁸, —S(O)₂NR¹²R¹², —NO₂,NR²¹C(O)OR¹⁷, —C(NR₁₂R¹²)═NR¹², —C(R¹³)═NOH; Q² is OH; W is O, S, orNR³; X² and X³ are independently O, S, S(O), S(O)₂, or CR³R¹⁶; with theproviso that at least one is S or SO₂; Y is —CR³═CR³—; Z¹ and Z² areindependently —HET(—R³—R⁵)—; and HET is the diradical of a benzene, apyridine, a furan, or a thiophene; or a pharmaceutically acceptable saltthereof.
 2. A method according to claim 1 wherein the mammal is man. 3.A method according to claim 1 wherein the compound has the formula:

wherein the substituents are as follows: * R¹ Y A B RS 7-Cl CH═CHSCH₂CHMeCO₂H (1,3-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂H (1,4-phe)CMe₂ OHRS 7-Cl CH═CH SCH₂CHEtCO₂ H (1,3-phe)CMe₂ OH RS 7-Cl CH═CH SCH₂CHEtCO₂ H(1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ OH S7-Cl C≡C SCH₂(S)CHMeCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHEtCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C S(CH₂)₂CO₂ H (CH₂)₂ (1,2-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NH₂ RS 7-Cl CH═CHSCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NHMe RS 7-Cl CH═CH SCH₂CHEtCO₂ H(CH₂)₂ (1,2-phe)CMe₂ NMe₂ RS 7-Br C≡C SCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂OH S 7-Cl CH═CH SCH₂CH(CH₂CH═CH₂)CO₂H (CH₂)₂ (1,2-phe)CMe₂ OH S 7-ClCH═CH SCH₂CHEtCO₂H (CH₂)₂(1,2-phe)C(CH₂OCH₂)OH


4. A method according to claim 3 wherein the mammal is man.
 5. A methodof treating a disorder selected from the group consisting of traumaticspinal cord injury, graying of scalp hair, herpes simplex, herpeszoster, Bell's palsy, multiple sclerosis, and Gillian-Barre, in a mammalcomprising administering to a mammal in need of such treatment atherapeutically effective amount of1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-2-hydroxy-2-propyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.6. A method according to claim 5 wherein the mammal is man.
 7. A methodfor the effective treatment and/or long term suppression of symptoms ofHerpes virus infection in a mammal, such a method being comprised ofadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound having the formula:

wherein: R¹ is H, halogen, —CF₃, —CN, —NO₂, or N₃; R² is lower alkyl,lower alkenyl, lower alkynyl, —CF₃, —CH₂F, —CHF₂, CH₂CF₃, substituted orunsubstituted phenyl, substituted or unsubstituted benzyl, substitutedor unsubstituted 2-phenethyl, or two R² groups joined to the same carbonto form a carbocyclic ring of up to 8 members; R³ is H or R²; R⁴ ishalogen, —NO₂, —CN, —OR³, —SR³, NR³R³, NR³C(O)R⁷or R³; R⁵ is H, halogen,—NO₂, —N₃, —CN, —SR², —NR³R³,—OR³, lower alkyl, or —C(O)R³; R⁶ is—(CH₂)_(s)—C(R⁷R⁷)—(CH₂)_(s)—R⁸ or —CH₂C(O)NR¹²R¹²; R⁷ is H or C₁-C₄alkyl; R⁸ is the radical W—R⁹; R⁹ contains up to 20 carbon atoms and is(1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclicor monocyclic carboxylic acid; R¹¹ is lower alkyl, —C(O)R¹⁴,unsubstituted phenyl, or unsubstituted benzyl; R¹² is H, or R¹¹; R¹³ islower alkyl, lower alkenyl, lower alkynyl, —CF₃ or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁴ is H or R¹³; R¹⁶ is H,C₁-C₄ alkyl, or OH; R¹⁷ is lower alkyl, lower alkenyl, lower alkynyl, orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁸ islower alkyl, lower alkenyl, lower alkynyl, —CF₃ or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁹ is lower alkyl, loweralkenyl, lower alkynyl, —CF₃ or substituted or unsubstituted phenyl,benzyl, or 2-phenethyl; R²¹ is H or R¹⁷; R²² is R⁴, CHR⁷OR³, or CHR⁷SR²;m is 0-8; m′ is 2 or 3; n and n′ are independently 0 or 1, p and p′ areindependently 0-8; m+n+p is 1-10 when r is 1 and X² is O, S, S(O), orS(O)₂; m+n+p is 0-10 when r is 1 and X² is CR³R¹⁶; m+n+p is 0-10 when ris 0; m′+n′+p′ is 2-10; r and r′ are independently 0 or 1; s is 0-3; Q¹is —C(O)OR^(3,) 1H (or 2H)-tetrazol-5-yl, —C(O)OR⁶, —C(O)NHS(O)₂R¹³,—CN, —C(O)NR¹²R¹², NR²¹S(O)₂R¹³, —NR¹²C(O)NR¹²R¹², —NR²¹C(O)R¹⁸,—OC(O)NR¹²R¹², —C(O)R¹⁹, —S(O)R¹⁸, —S(O)₂R¹⁸, —S(O)₂NR¹²R¹², —NO₂,—NR²¹C(O)OR¹⁷, —C(NR¹²R¹²)═NR¹², —C(R¹³)═NOH; Q² is OH; W is O, S, orNR³; X² and X³ are independently O, S, S(O), S(O)₂, or CR³R¹⁶; with theproviso that at least one is S or SO₂; Y is —CR³═CR³—; Z¹ and Z² areindependently —HET(—R³—R⁵)—; and HET is the diradical of a benzene, apyridine, a furan, or a thiophene; or a pharmaceutically acceptable saltthereof.
 8. A method as in claim 7 wherein the mammal is man.
 9. Amethod as in claim 8 wherein the Herpes virus is Herpes simplex I (HSVI), Herpes simplex II (HSV II) or Herpes zoster.
 10. A method as inclaim 8 or 9 wherein said compound has the formula:

wherein the substituents are as follows: * R¹ Y A B RS 7-Cl CH═CHSCH₂CHMeCO₂H (1,3-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂H (1,4-phe)CMe₂ OHRS 7-Cl CH═CH SCH₂CHEtCO₂ H (1,3-phe)CMe₂ OH RS 7-Cl CH═CH SCH₂CHEtCO₂ H(1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ OH S7-Cl C≡C SCH₂(S)CHMeCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHEtCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C S(CH₂)₂CO₂ H (CH₂)₂ (1,2-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NH₂ RS 7-Cl CH═CHSCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NHMe RS 7-Cl CH═CH SCH₂CHEtCO₂ H(CH₂)₂ (1,2-phe)CMe₂ NMe₂ RS 7-Br C≡C SCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂OH S 7-Cl CH═CH SCH₂CH(CH₂CH═CH₂)CO₂H (CH₂)₂ (1,2-phe)CMe₂ OH S 7-ClCH═CH SCH₂CHEtCO₂H (CH₂)₂(1,2-phe)C(CH₂OCH₂)OH


11. A method as in claim 8 or 9 wherein said compound is1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.12. A method for the effective treatment of traumatic spinal cord injuryin a mammal, such a method comprised of administering to a mammal inneed of such treatment a therapeutically effective amount of a compoundhaving the formula:

wherein: R¹ is H, halogen, —CF₃, —CN, —NO₂, or N₃; R² is lower alkyl,lower alkenyl, lower alkynyl, —CF₃, —CH₂F, —CHF₂, CH₂CF₃, substituted orunsubstituted phenyl, substituted or unsubstituted benzyl, substitutedor unsubstituted 2-phenethyl, or two R² groups joined to the same carbonto form a carbocyclic ring of up to 8 members; R³ is H or R²; R⁴ ishalogen, —NO₂, —CN, —OR³, —SR³, NR³R³, NR³C(O)R⁷or R³; R⁵ is H, halogen,—NO₂, —N₃, —CN, —SR², —NR³R³, —OR³, lower alkyl, or —C(O)R³; R⁶ is—(CH₂)_(s)—C(R⁷R⁷)—(CH₂)_(s)—R⁸ or —CH₂C(O)NR¹²R¹²; R⁷ is H or C₁-C₄alkyl; R⁸ is the radical W—R⁹; R⁹ contains up to 20 carbon atoms and is(1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclicor monocyclic carboxylic acid; R¹¹ is lower alkyl, —C(O)R¹⁴,unsubstituted phenyl, or unsubstituted benzyl; R¹² is H, or R¹¹; R¹³ islower alkyl, lower alkenyl, lower alkynyl, —CF₃ or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁴ is H or R¹³; R¹⁶ is H,C₁-C₄ alkyl, or OH; R¹⁷ is lower alkyl, lower alkenyl, lower alkynyl, orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁸ islower alkyl, lower alkenyl, lower alkynyl, —CF₃ or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁹ is lower alkyl, loweralkenyl, lower alkynyl, —CF₃ or substituted or unsubstituted phenyl,benzyl, or 2-phenethyl; R²¹ is H or R¹⁷; R²² is R⁴, CHR⁷OR³, or CHR⁷SR²;m is 0-8; m′ is 2 or 3; n and n′ are independently 0 or 1; p and p′ areindependently 0-8; m+n+p is 1-10 when r is 1 and X² is O, S, S(O), orS(O)₂; m+n+p is 0-10 when r is 1 and X² is CR³R¹⁶; m+n+p is 0-10 when ris 0; m′+n′+p′ is 2-10; r and r′ are independently 0 or 1; s is 0-3; Q¹is —C(O)OR^(3,) 1H (or 2H)-tetrazol-5-yl, —C(O)OR⁶, —C(O)NHS(O)₂R¹³,—CN, —C(O)NR¹²R¹², NR²¹S(O)₂R¹³, —NR¹²C(O)NR¹²R¹², —NR²¹C(O)R¹⁸,—OC(O)NR¹²R¹², —C(O)R¹⁹, —S(O)R¹⁸, —S(O)₂R¹⁸, —S(O)₂NR¹²R¹², —NO₂,—NR²¹C(O)OR¹⁷, —C(O)OR¹⁷, —C(NR¹²R¹²)═NR¹², —C(R¹³)═NOH; Q² is OH; W isO, S, or NR³; X²and X³ are independently O, S, S(O), S(O)₂, or CR³R¹⁶;with the proviso that at least one is S or SO₂; Y is —CR³═CR³—; Z¹ andZ² are independently —HET(—R³—R⁵)—; and HET is the diradical of abenzene, a pyridine, a furan, or a thiophene; or a pharmaceuticallyacceptable salt thereof.
 13. A method as in claim 12 wherein the mammalis man.
 14. A method as in claim 13 wherein said compound has theformula:

wherein the substituents are as follows: * R¹ Y A B RS 7-Cl CH═CHSCH₂CHMeCO₂H (1,3-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂H (1,4-phe)CMe₂ OHRS 7-Cl CH═CH SCH₂CHEtCO₂ H (1,3-phe)CMe₂ OH RS 7-Cl CH═CH SCH₂CHEtCO₂ H(1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ OH S7-Cl C≡C SCH₂(S)CHMeCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHEtCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C S(CH₂)₂CO₂ H (CH₂)₂ (1,2-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NH₂ RS 7-Cl CH═CHSCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NHMe RS 7-Cl CH═CH SCH₂CHEtCO₂ H(CH₂)₂ (1,2-phe)CMe₂ NMe₂ RS 7-Br C≡C SCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂OH S 7-Cl CH═CH SCH₂CH(CH₂CH═CH₂)CO₂H (CH₂)₂ (1,2-phe)CMe₂ OH S 7-ClCH═CH SCH₂CHEtCO₂H (CH₂)₂(1,2-phe)C(CH₂OCH₂)OH


15. A method as in claim 13 wherein said compound is1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.16. A method for the treatment and long-term suppression, in a mammal,of symptoms of neuronal inflammatory conditions not due to repetitivemotion, said conditions being selected from the group consisting of aHerpes virus infection, traumatic spinal cord injury and graying ofscalp hair, such method comprising administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compound havingthe formula:

wherein: R is H, halogen, —CF₃, —CN, —NO₂, or N₃; R² is lower alkyl,lower alkenyl, lower alkynyl, —CF₃, —CH₂F, —CHF₂, CH₂CF₃, substituted orunsubstituted phenyl, substituted or unsubstituted benzyl, substitutedor unsubstituted 2-phenethyl, or two R² groups joined to the same carbonto form a carbocyclic ring of up to 8 members; R³ is H or R²; R⁴ ishalogen, —NO₂, —CN, —OR³, —SR³, NR³R³, NR³C(O)R⁷ or R³; R⁵ is H,halogen, —NO₂, —N₃, —CN, —SR², —NR³R³, —OR³, lower alkyl, or —C(O)R³; R⁶is —(CH₂)_(s)—C(R⁷R7)—(CH₂)_(s)—R⁸ or —CH₂C(O)NR¹²R¹²; R⁷ is H or C₁-C₄alkyl; R⁸ is the radical W—R⁹; R⁹ contains up to 20 carbon atoms and is(1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclicor monocyclic carboxylic acid; R¹¹ is lower alkyl, —C(O)R¹⁴,unsubstituted phenyl, or unsubstituted benzyl; R¹² is H, or R¹¹; R¹³ islower alkyl, lower alkenyl, lower alkynyl, —CF₃ or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁴ is H or R¹³; R¹⁶ is H,C₁-C₄ alkyl, or OH; R¹⁷ is lower alkyl, lower alkenyl, lower alkynyl, orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁸ islower alkyl, lower alkenyl, lower alkynyl, —CF₃ or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁹ is lower alkyl, loweralkenyl, lower alkynyl, —CF₃ or substituted or unsubstituted phenyl,benzyl, or 2-phenethyl; R²¹ is H or R⁷; R²² is R⁴, CHR⁷OR³, or CHR⁷SR²;m is 0-8; m′ is 2 or 3; n and n′ are independently 0 or 1; p and p′ areindependently 0-8; m+n+p is 1-10 when r is 1 and X² is O, S, S(O), orS(O)₂; m+n+p is 0-10 when r is 1 and X² is CR³R¹⁶; m+n+p is 0-10 when ris 0; m′+n′+p′ is 2-10; r and r′ are independently 0 or 1; s is 0-3; Q¹is —C(O)OR^(3,) 1H (or 2H)-tetrazol-5-yl, —C(O)OR⁶, —C(O)NHS(O)₂R¹³,—CN, —C(O)NR¹²R¹², NR²¹S(O)₂R¹³, —NR¹²C(O)NR¹²R¹², —NR²¹C(O)R¹⁸,—OC(O)NR¹²R¹², —C(O)R¹⁹, —S(O)R¹⁸, —S(O)₂R¹⁸, —S(O)₂NR¹²R¹², —NO₂,—NR²¹C(O)OR¹⁷, —C(NR¹²R¹²)═NR¹², —C(R¹³)═NOH; Q² is OH; W is O, S, orNR³; X² and X³ are independently O, S, S(O), S(O)₂, or CR³R¹⁶; with theproviso that at least one is S or SO₂; Y is —CR³═CR³═; Z¹ and Z² areindependently —HET(—R³—R⁵)—; and HET is the diradical of a benzene, apyridine, a furan, or a thiophene; or a pharmaceutically acceptable saltthereof.
 17. A method as in claim 16 wherein the mammal is man.
 18. Amethod as in claim 17 wherein the neuronal inflammatory condition isMultiple sclerosis, Guillian-Barre syndrome or Bell's palsy.
 19. Amethod as in claim 17 or 18 wherein said compound has the formula:

wherein the substituents are as follows: * R¹ Y A B RS 7-Cl CH═CHSCH₂CHMeCO₂H (1,3-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂H (1,4-phe)CMe₂ OHRS 7-Cl CH═CH SCH₂CHEtCO₂ H (1,3-phe)CMe₂ OH RS 7-Cl CH═CH SCH₂CHEtCO₂ H(1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ OH S7-Cl C≡C SCH₂(S)CHMeCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHEtCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C S(CH₂)₂CO₂ H (CH₂)₂ (1,2-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NH₂ RS 7-Cl CH═CHSCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NHMe RS 7-Cl CH═CH SCH₂CHEtCO₂ H(CH₂)₂ (1,2-phe)CMe₂ NMe₂ RS 7-Br C≡C SCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂OH S 7-Cl CH═CH SCH₂CH(CH₂CH═CH₂)CO₂H (CH₂)₂ (1,2-phe)CMe₂ OH S 7-ClCH═CH SCH₂CHEtCO₂H (CH₂)₂(1,2-phe)C(CH₂OCH₂)OH


20. A method as in claim 17 or 18 wherein said compound is1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.21. A method for inhibiting, in a mammal, the graying of scalp hairwhich comprises administering to a mammal in need of such treatment atherapeutically effective amount of a compound having the formula:

wherein: R is H, halogen, —CF₃, —CN, —NO₂, or N₃; R² is lower alkyl,lower alkenyl, lower alkynyl, —CF₃, —CH₂F, —CHF₂, CH₂CF₃, substituted orunsubstituted phenyl, substituted or unsubstituted benzyl, substitutedor unsubstituted 2-phenethyl, or two R² groups joined to the same carbonto form a carbocyclic ring of up to 8 members; R³ is H or R²; R⁴ ishalogen, —NO₂, —CN, —OR³, —SR³, NR³R³, NR³C(O)R⁷ or R³; R⁵ is H,halogen, —NO₂, —N₃, —CN, —SR², —NR³R³, —OR³, lower alkyl, or —C(O)R³; R⁶is —(CH₂)_(s)—C(R⁷R⁷)—(CH₂)_(s)—R⁸ or —CH₂C(O)NR¹²R²; R⁷ is H or C₁-C₄alkyl; R⁸ is the radical W—R⁹ R⁹ contains up to 20 carbon atoms and is(1) an alkyl group or (2) an alkylcarbonyl group of an organic acyclicor monocyclic carboxylic acid; R¹¹ is lower alkyl, —C(O)R¹⁴,unsubstituted phenyl, or unsubstituted benzyl; R¹² is H, or R¹¹; R¹³ islower alkyl, lower alkenyl, lower alkynyl, —CF₃ or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁴ is H or R¹³; R¹⁶ is H,C₁-C₄ alkyl, or OH; R¹⁷ is lower alkyl, lower alkenyl, lower alkynyl, orsubstituted or unsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁸ islower alkyl, lower alkenyl, lower alkynyl, —CF₃ or substituted orunsubstituted phenyl, benzyl, or 2-phenethyl; R¹⁹ is lower alkyl, loweralkenyl, lower alkynyl, —CF₃ or substituted or unsubstituted phenyl,benzyl, or 2-phenethyl; R²¹ is H or R¹⁷; R²² is R⁴, CHR⁷OR³, or CHR⁷SR²;m is 0-8; m′ is 2 or 3; n and n′ are independently 0 or 1; p and p′ areindependently 0-8; m+n+p is 1-10 when r is 1 and X² is O, S, S(O), orS(O)₂; m+n+p is 0-10 when r is 1 and X² is CR³R¹⁶; m+n+p is 0-10 when ris 0; m′+n′+p′ is 2-10; r and r′ are independently 0 or 1; s is 0-3; Q¹is —C(O)OR^(3,) 1H (or 2H)-tetrazol-5-yl, —C(O)OR⁶, —C(O)NHS(O)₂R¹³,—CN, —C(O)NR¹²R¹², NR²¹S(O)₂R¹³, —NR¹²C(O)NR¹²R¹², —NR²¹C(O)R¹⁸,—OC(O)NR¹², —C(O)R¹⁹, —S(O)R¹⁸, —S(O)₂R¹⁸, —S(O)₂NR¹²R¹², —NO₂,—NR²¹C(O)OR¹⁷, —C(NR¹²R¹²)═NR¹², —C(R¹³)═NOH; Q² is OH; W is O, S, orNR³; X² and X³ are independently O, S, S(O), S(O)₂, or CR³R¹⁶; with theproviso that at least one is S or SO₂; Y is —CR³═CR³—; Z¹ and Z² areindependently —HET(—R³—R⁵)—; and HET is the diradical of a benzene, apyridine, a furan, or a thiophene; or a pharmaceutically acceptable saltthereof.
 22. A method as in claim 21 wherein the mammal is man.
 23. Amethod as in claim 21 or 22 wherein the compound has the formula:

wherein the substituents are as follows: * R¹ Y A B RS 7-Cl CH═CHSCH₂CHMeCO₂H (1,3-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂H (1,4-phe)CMe₂ OHRS 7-Cl CH═CH SCH₂CHEtCO₂ H (1,3-phe)CMe₂ OH RS 7-Cl CH═CH SCH₂CHEtCO₂ H(1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ OH S7-Cl C≡C SCH₂(S)CHMeCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C SCH₂CHEtCO₂H (CH₂)₂ (1,2-phe)CMe₂ OH RS 7-Cl C≡C S(CH₂)₂CO₂ H (CH₂)₂ (1,2-phe)CMe₂OH RS 7-Cl CH═CH SCH₂CHMeCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NH₂ RS 7-Cl CH═CHSCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂ NHMe RS 7-Cl CH═CH SCH₂CHEtCO₂ H(CH₂)₂ (1,2-phe)CMe₂ NMe₂ RS 7-Br C≡C SCH₂CHEtCO₂ H (CH₂)₂ (1,2-phe)CMe₂OH S 7-Cl CH═CH SCH₂CH(CH₂CH═CH₂)CO₂H (CH₂)₂ (1,2-phe)CMe₂ OH S 7-ClCH═CH SCH₂CHEtCO₂H (CH₂)₂(1,2-phe)C(CH₂OCH₂)OH


24. A method as in claim 21 or 22 wherein the compound is1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof.25. An article of manufacture for human pharmaceutical use, comprisingpackaging material and a container comprising 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl) phenyl)propyl)thio)methyl)cyclopropaneacetic acid or a pharmaceutically acceptable salt thereof,wherein said packaging material comprises a label which indicates thatsaid cyclopropaneacetic acid, or said pharmaceutically acceptable saltthereof, is suitable for treatment, or alleviation of symptoms, of oneor more disorders selected from the group consisting of traumatic spinalcord injury, graying of scalp hair, herpes simplex, herpes zoster,Bell's palsy, multiple sclerosis, and Gillian-Barre.
 26. An articleaccording to claim 25, wherein said container is selected from the groupconsisting of a blister pack, a bottle and a silica gel desiccantcanister.